Bone remodeling is the dynamic process whereby skeletal mass and architecture are renewed and maintained. This renewal and maintenance is a balance between bone resorption and bone formation, with the osteoclast and the osteoblast considered the two key participants in the remodeling process. The osteoclast initiates the remodeling cycle by resorbing a cavity in the bone which is subsequently refilled when the osteoblast synthesizes and deposits new bone matrix into the excavation. The activities of osteoclast and osteoblast are regulated by complex interactions between systemic hormones and the local production of growth factors and cytokines at active remodeling sites
Imbalances in bone remodeling are associated with such conditions as osteoporosis, Paget's disease, and hyperparathyrodism. Osteoporosis, characterized by a decrease in the skeletal mass, is one of the most common diseases of postmenopausal women and is often the cause of debilitating and painful fractures of the spine, hip and wrist.
Approximately 25% of all postmenopausal women suffer from osteoporosis, and it is generally accepted that the etiology of the disease involves the reduction of circulating estrogens (Komm et al., Science 241:81-84, 1988) Komm et al. further report that the proportion of Caucasian women in the United States who are at risk for a hip fracture is 15%, or 247,000 hip fractures per year in women over the age of 45.
The costs of osteoporosis, both personal and financial, are enormous. In 1984, 145,000 in-patient fracture reductions and 107,000 hip arthroplasties and replacements were performed on American women over 65 years of age. Among patients who lived alone prior to hip fracture, 15% to 20% required long-term care as a result of the fracture and one year after the fracture had still not regained their independence. The total financial cost of osteoporosis treatment, including fractures, in the United States in 1986 was 7-10 billion dollars (Peck et al., Am.J.Med. 84:275-282,1988).
Bone loss associated with osteoporosis has been arrested by the administration of exogeneous estrogens. To be effective, estrogen therapy must begin within a few years of the onset of menopause, and should continue for 10 to 15 years, according to Thorneycroft (Am.J.Obstet.Gynecol. 160:1306.1310m 1989), While there are several different types of estrogens, 17-.beta.-estradiol is the primary estrogen found naturally occurring in premenopausal women and is often the compound of choice for therapetic use. At the recommended dose, however, there are significant side effects, the most distrubing being the well-established correlation of estrogen therapy with endometrial and brest cancers. The incidence of carcinoma is both dose-dependent and duration-dependent.
3,4-diarylchromans and their salts are useful within human and veterinary medicine for the regulation of bone metabolism. These compounds may be used, for example, in the treatment of patients suffering from bone loss due to osteoporosis (including post-menopausal osteoporosis and glucocorticoid-related osteoporosis), Paget's disease, hyperparathyroidism, hypercalcemia of malignancy and other conditions characterized by excessive rates of bone resorption and/or decreased rates of bone formation.
Avoidance of the cancer risk has been achieved by the concomitant use of a progestogen with estrogen. This combination , however, causes menses to return, which many women find unacceptable. A further disadvantage is that the longterm effects of the progestogen have not been fully determined. Thus, a large population of women require alternatives to hormone replacement therapies that can safely prevent the rapid bone loss that accompanies the menopause.
The formula I compounds are described in U.S. Pat. No. 5,280,040. This patent describes the preparation of these compounds, as well as their use in reducing bone loss. The preparation of pharmaceutical compositions is also described.
Centchroman, which is 3,4-trans-2,2-dimethyl-3-phenyl-4-4-(2-pyrrolidin-1-yl)ethoxy)phenyl!-7-m ethoxychroman, is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al U.S. Pat. No. 4,447,622; Singh et al., Acta Endocrinal (Copenh) 126 (1992), 444-450; Grubb, Curr Opin Obstet Gynecol 3(1991), 491-495; Sankaran et al., Contraception 9(1974), 279-289; Indian Patent Specification No. 129187). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781-783). Recently, centchroman as a racemate has been found as a potent cholesterol lowering pharmaceutical agent expressed by a significant decrease of the serum concentrations (S. D. Bain et al., J Min Bon Res 9 (1994), S 394).
Levormeloxifene, (-)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-2-(pyrrolidin-1-yl)e thoxy!phenyl}chromane, is a particular preferred compound from this series of 3,4-diarylchromans. Levormeloxifene may be used in human and veterinary medicine for the regulation of bone metabolism. It may be used, for example, in the treatment of patients suffering from bone loss due to osteoporosis (including post-menopausal osteoporosis and glucocorticoid-related osteoporosis), Paget's disease, hyperparathyroidism, hypercalcemia of malignancy and other conditions characterized by excessive rates of bone resorption and/or decreased rates of bone formation.
The 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Pat. No. 3,340,276 to Carney et al., U.S. Pat. No. 3,822,287 to Bolger, and Ray et al., J Med Chem 19 (1976), 276-279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is disclosed in U.S. Pat. No. 3,822,287. The optically active d- and I-enantiomers may be prepared as disclosed by Salman et al. in U.S. Pat. No. 4,447,622 (incorporated herein by reference) by forming an optically active acid salt which is subjected to alkaline hydrolysis to produce the desired enantiomer. The resolvation of (+/-)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-2-(pyrrolidin-1-yl)e thoxy!phenyl}chromane in its optical antipodes is described in U.S. Pat. No. 4,447,622 incorporated herein by reference. Example 1 of U.S. Pat. No. 4,447,622 describes the preparation of the minus enantiomer, shown by formula II: ##STR1## (In this specification, the compound of formula II is referred to as levormeloxifene.)
In example 2 of U.S. Pat. No. 4,447,622, levormeloxifene is obtained as the free base and the hydrochloride salt. The compounds of formula I may be administered as pharmaceutically acceptable salts. A particularly useful pharmaceutically acceptable salt of levormeloxifene is the hydrogen fumarate salt (in this specification, this compound is referred to as levormeloxifene fumarate.). This salt form is prepared by dissolving fumaric acid and (-)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-2-(pyrrolidin-1-yl)e thoxy!phenyl}chromane in a common solvent such as e.g. methanol, and crystallizing the resulting salt from the solution.
U.S. Pat. No. 5,280,040 and U.S. Pat. No. 5,464,862 discloses a class of 3,4-diarylchromans and their salts useful for reducing bone loss.
The free base has a very poor solubility in water and the hydrochloride salt has some pharmaceutically undesirable properties. The hydrochloride salt is hygroscopic, it is quite heavy soluble in water and it forms a solid gel in aqueous suspension.
For commercial use it is important to have a physiologically acceptable salt with good stability, non-hygroscopicity, good bioavailability, good handling properties, and a reproducible crystalline form.
The transdermal route for delivery of drugs provides many advantages such as noninvasive drug delivery, no first pass effect, lower dose and better compliance for patients with dosing problems as to conventional dosing forms, i.e. tablets or capsules.
Transdermal systems for delivering a wide variety of drugs or other agents are described in i.a. U.S. Pat. No. 4,978,532 and in PCT publication WO 91/09592.
Drugs can be delivered into the systemic circulation via the human skin membrane with low daily doses because first pass hepatic metabolism is avoided (Todd P. A. & Goa K. L., Drugs 40(4): p. 583-607 (1990)). This may be convenient because low-dose forms may avoid some of the side effects of higher dose oral therapy.